17 October 2019 EMA/CHMP/602404/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment report BAQSIMI International non-proprietary name: glucagon Procedure No. EMEA/H/C/003848/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition ........................................................................................... 9 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Biologic features, Aetiology and pathogenesis ..................................................... 10 2.1.4. Clinical presentation, diagnosis .......................................................................... 10 2.1.5. Management ................................................................................................... 10 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction .................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 13 General information .................................................................................................. 13 Manufacture, characterisation and process controls ....................................................... 13 Specification............................................................................................................. 14 Stability ................................................................................................................... 14 2.2.3. Finished Medicinal Product ................................................................................ 15 Description of the product and Pharmaceutical development .......................................... 15 Manufacture of the product and process controls .......................................................... 16 Product specification ................................................................................................. 16 Stability of the product .............................................................................................. 17 Adventitious agents ................................................................................................... 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.6. Recommendation for future quality development ................................................. 18 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction .................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics............................................................................................. 20 2.3.4. Toxicology ...................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 24 2.3.6. Discussion on non-clinical aspects...................................................................... 24 2.3.7. Conclusion on the non-clinical aspects ................................................................ 25 2.4. Clinical aspects .................................................................................................. 26 2.4.1. Introduction .................................................................................................... 26 2.4.2. Pharmacokinetics............................................................................................. 27 2.4.3. Pharmacodynamics .......................................................................................... 38 2.4.4. Discussion on clinical pharmacology ................................................................... 42 2.4.5. Conclusions on clinical pharmacology ................................................................. 44 2.5. Clinical efficacy .................................................................................................. 45 2.5.1. Dose response study(ies) ................................................................................. 45 Assessment report EMA/CHMP/602404/2019 Page 2/116 2.5.2. Main study(ies) ............................................................................................... 45 Summary of main studies .......................................................................... 74 2.5.3. Supportive study(ies) ....................................................................................... 78 2.5.4. Discussion on clinical efficacy ............................................................................ 85 2.5.5. Conclusions on the clinical efficacy ..................................................................... 88 2.6. Clinical safety .................................................................................................... 89 2.6.1. Discussion on clinical safety ............................................................................ 101 2.6.2. Conclusions on the clinical safety ..................................................................... 103 2.7. Risk Management Plan ...................................................................................... 103 2.8. Pharmacovigilance ............................................................................................ 104 2.9. Product information .......................................................................................... 105 2.9.1. User consultation ........................................................................................... 105 3. Benefit-Risk Balance............................................................................ 105 3.1. Therapeutic Context ......................................................................................... 105 3.1.1. Disease or condition ....................................................................................... 105 3.1.2. Available therapies and unmet medical need ..................................................... 106 3.1.3. Main clinical studies ....................................................................................... 106 3.2. Favourable effects ............................................................................................ 107 3.3. Uncertainties and limitations about favourable effects ........................................... 108 3.4. Unfavourable effects ......................................................................................... 109 3.5. Uncertainties and limitations about unfavourable effects ....................................... 109 3.6. Effects Table .................................................................................................... 111 3.7. Benefit-risk assessment and discussion ............................................................... 113 3.7.1. Importance of favourable and unfavourable effects ............................................ 113 3.7.2. Balance of benefits and risks ........................................................................... 113 3.7.3. Additional considerations on the benefit-risk balance ......................................... 113 3.8. Conclusions ..................................................................................................... 114 4. Recommendations ............................................................................... 114 Assessment report EMA/CHMP/602404/2019 Page 3/116 List of abbreviations ACE affinity capture elution ADA antidrug antibody AP-HIRS affinity-purified, hyper-immune rabbit serum API active pharmaceutical ingredient ASMF active substance master file AUC(0-∞) area under the concentration versus time curve from zero to infinity AUC(0-tlast) area under the concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration CAD collisionally activated dissociation CQA critical quality attribute Cmax maximum plasma concentration CL/F apparent total body clearance of drug calculated after extra-vascular administration DCP dodecylphosphocoline DSC differential scanning calorimetry ESI electrospray ionisation ESI-MS electrospray ionisation mass spectrometry